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Researchers from The University of Manchester and The Christie NHS Foundation Trust — both part of Manchester Cancer Research Centre — say the test could be developed and used in hospitals within the next few years.

It would mean medics could see which patients could benefit from blood vessel-targeting drugs — such as bevacizumab — in addition to conventional therapy. Meanwhilehile others who are not going to benefit would be spared the time and side effects associated with having the drug.

The test would also help to reduce the cost to the NHS. Ovarian cancer has seen little increase in survival rates over the last few decades and scientists are seeking new treatment strategies to improve the standard approach of surgery and chemotherapy.

A recent advance has been to target the development of new blood vessels within the tumor — preventing the cancer from receiving the nutrients it needs to grow. Bevacizumab, one of the blood vessel-targeting drugs, has shown significant but modest improvements in patient survival so doctors are seeking ways to predict which patients are most likely to gain an advantage from this type of drug.

The research team looked at blood samples from patients enrolled in an international trial of bevacizumab. These patients received either standard chemotherapy treatment alone or chemotherapy plus the blood vessel-targeting drug.

Professor Gordon Jayson, Professor of Medical Oncology at The University of Manchester and Honorary Consultant at The Christie who jointly led the study, said: “We are keen to identify predictive biomarkers — measures that can indicate how well a patient will respond to treatment — so we can better target these drugs to patients most likely to benefit.”We investigated levels of a range of proteins in patients’ pre-treatment blood samples to see if any were associated with improved survival.”

The findings, published recently in the journal Clinical Cancer Research, show that two particular proteins — Ang1 and Tie2 — could be used in combination to predict patient response. Patients with high levels of Ang1 and low levels of Tie2 were most likely to benefit from bevacizumab.

Both these proteins are involved in controlling the formation of new blood vessels. Conversely, they found that patients with high levels of both proteins did not benefit from the additional drug.

Study co-author Professor Caroline Dive, from the Cancer Research UK Manchester Institute based at The University of Manchester, added: “We will now look to further explore the potential of using a blood test to personalise treatment for ovarian cancer patients.

Moving towards a more individualized treatment plan specific for each patient and their particular tumor is key to improving outcomes for patients while sparing those unlikely to benefit from potential side effects of therapy.”

“Scientists have long observed that human and mouse cancers contain a lot of nerves in and around the tumor cells,” said Dr. Wang, the Dorothy L. and Daniel H. Silberberg Professor of Medicine at Columbia’s Herbert Irving Comprehensive Cancer Center. “We wanted to understand more about the role of nerves in the initiation and growth of cancer, by focusing on stomach cancer.”

Stomach cancer is the fourth-leading type of cancer and the second-highest contributor to cancer mortality worldwide, with a 5-year survival rate of less than 25 percent.

Using three different mouse models of stomach cancer, Dr. Wang’s team found that when they performed a procedure called a vagotomy to cut the nerves, the surgery significantly slowed tumor growth and increased survival rates. Removing nerve connections from only one side of the stomach allowed cancer to continue growing on the other side (with the intact nerves), providing further evidence of the importance of nerves in tumor growth.

Dr. Wang’s team then tried to block transmission of nerve signals pharmacologically. They found that when they injected Botox® into mice, the drug proved to be as effective as surgery at reducing stomach cancer growth. “We found that blocking the nerve signals makes the cancer cells more vulnerable — it removes one of the key factors that regulate their growth,” said Dr. Wang.

Botox® prevents nerve cells from releasing a neurotransmitter called acetylcholine. In the case of cosmetic treatment, for example, blocking acetylcholine helps to lessen facial wrinkles by causing temporary paralysis of the muscles. Because acetylcholine also ordinarily stimulates cell division, using Botox® to prevent acetylcholine release might help slow the growth of cancer.

Dr. Wang’s team also found evidence of the effectiveness of targeting nerves for cancer treatment in human patients when they compared 37 patients who had a recurrence of stomach cancer many years after surgery. Of the 13 patients who had had a vagotomy as part of their procedure, in all but one case, tumors did not develop in regions where the nerve connections had been severed. By contrast, tumors were found in the same region of the stomach in all 24 patients who had not had a vagotomy.

Next, Dr. Wang’s team plans to investigate the effectiveness of nerve-targeted therapy used in combination with other cancer treatments. Initial experiments have shown that blocking nerves makes cancer cells more vulnerable to chemical agents. Botox® used in combination with chemotherapy in mice increases survival rates up to 35 percent, compared with chemotherapy alone.

A limitation of the current studies is that they focus primarily on early stages of stomach cancer. “In the future, we’d really like to look at how we can use this method of targeting nerves to stop the growth of more advanced tumors,” Dr. Wang said. His laboratory hopes to develop drugs that block neurotransmitter receptors. This approach would be more effective than surgery or Botox® on more invasive forms on cancer, as such drugs would be able reach cells that have broken away from the main tumor.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, professor of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, who is primary author of the peer reviewed article. “These cells are resistant to multiple types of standard chemotherapeutic agents because of over-expression of Myeloid Cell Leukemia-1 (Mcl-1), however, Mcl-1 expression plummets when we inhibit one particular enzyme and then cancer cells subsequently die.”

The Mcl-1 protein is frequently over-expressed in cancer; it is present not only in leukemia and lymphoma but also in a host of solid tumors. While Mcl-1 is expressed in a highly-controlled fashion in normal cells, its over-expression and lack of destruction maintains the viability of cancer cells and renders them resistant to chemotherapy. When high levels of this protein are maintained, the patient’s cancer cells survive multiple types of drug treatment.

The research found that an enzyme that removes phosphate groups from Mcl-1 is critical in terms of maintaining its expression in cancer. This enzyme, known as protein phosphatase 2A (PP2A), can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids Proline, glutamic acid, Serine, and Threonine). Inhibition of the removal of phosphate groups, such as at Threonine-163 and Serine-159, targets the Mcl-1 protein for rapid destruction and, shortly thereafter, the cancer cells die.

“PP2A is a complex multi-subunit enzyme and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” said Craig. “This could give a more specific way of causing Mcl-1 destruction.”